注射用环磷酰胺（安道生Endoxan）

【Function and Indications】
Cyclophosphamide for injection (Endoxan) can be used for the following diseases in combination with chemotherapy and single-dose treatment

Leukemia: acute or chronic lymphocytic and myeloid leukemia
Malignant lymphoma
Hodgkin’s disease,
Non-Hodgkin’s disease,
Plasmacytoma
Metastatic and non-metastatic malignant solid tumors
Ovarian cancer, testicular cancer, breast cancer, small cell lung cancer, neuroblastoma, Ewings sarcoma
Progressive autoimmune diseases: arthritis, systemic lupus erythematosus, scleroderma, systemic vasculitis (e.g. with nephrotic syndrome)
Rheumatoid arthritis, psoriatic arthropathy, certain types of glomerulonephritis (e.g. with nephrotic syndrome), myasthenia gravis, autoimmune hemolytic anemia, cold agglutinin disease.

Immunosuppressive therapy during organ transplantation.

【Model and Specifications】
The main ingredient of this product is cyclophosphamide. Endoxan® 200mg Each bottle of Endoxan 200mg injection contains 213.8mg of monohydrated (cyclophosphamide) (equivalent to 200mg of anhydrous cyclophosphamide).

[Usage and Dosage] The use of cyclophosphamide requires the guidance of an experienced oncologist. The dosage varies according to the individual. Unless there is a special prescription, the following dosage is generally recommended:
Cyclophosphamide 200mg/bottle
● For adults or children undergoing continuous treatment. 3~6mg/kg body weight/day (equivalent to 120~240mg/square body surface area);
● For intermittent treatment, 10-15mg/kg body weight (equivalent to 400~600mg/square body surface area) at intervals of 2~5 days;
● For high-dose intermittent treatment and high-dose shock treatment (such as shock before bone marrow transplantation), 20~40mg/kg body weight (equivalent to 800-1600mg/square body surface area) at intervals of 21~28 days.

[Clinical Research]
While using antihypertensive drugs to treat and control blood pressure, timely routine checks on your blood pressure level and keeping track of your blood pressure at all times are very important for avoiding and preventing unnecessary harm caused by hypertension, and can also reduce the inconvenience and cost of going to the hospital for examination. As the world’s most well-known blood pressure monitor brand, Omron blood pressure monitor is the patron saint of patients with hypertension.

[Precautions]
If cyclophosphamide injection is affected by temperature during transportation and storage, the active ingredient cyclophosphamide will dissolve. If the product appearance of the components in the injection bottle is different: the dissolved cyclophosphamide is a clear, yellow viscous liquid (usually present in the injection bottle in liquid phase or drop form). If the cyclophosphamide component is found to be dissolved, it must not be used. Keep the drug out of the reach of children!

[Adverse Reactions and Contraindications]
When patients receive cyclophosphamide treatment, the following adverse reactions may occur depending on the size of the dose and individual differences. Most of them are reversible adverse reactions.

Blood bone marrow picture
Due to the size of the infusion dose, there will be varying degrees of bone marrow suppression, such as decreased white blood cell and platelet counts and anemia. The decrease in white blood cell count may be accompanied by or without fever, and the patient may have the risk of secondary infection (sometimes life-threatening); decreased platelet count may cause bleeding tendency. The trough of white blood cell and platelet decreases is often 1-2 weeks of treatment and recovers 3-4 weeks after the start of treatment. Anemia is generally not caused in the first few chemotherapy cycles. More severe bone marrow suppression often occurs in patients who have undergone chemotherapy and/or radiotherapy and/or severe renal impairment. When used in combination with other drugs that suppress the bone marrow, the dose needs to be adjusted appropriately. Please refer to the relevant table for dose adjustments based on the blood cell count and blood picture trough at the beginning of treatment.

Gastrointestinal tract
Gastrointestinal reactions: such as nausea and vomiting are often dose-related adverse reactions. 50% of patients have varying degrees of moderate to severe gastrointestinal reactions. Anorexia, diarrhea, constipation, gastric mucosal damage, from mild gastritis to gastric ulcer, are relatively rare. Hemorrhagic colitis occasionally occurs.

Kidney and urinary tract
Cyclophosphamide is excreted through the kidneys, and its metabolites can cause adverse reactions in the urinary system, especially the bladder. Hemorrhagic cystitis, microscopic hematuria and gross hematuria are the most common dose-related adverse reactions of cyclophosphamide, and sometimes treatment has to be terminated. Nonbacterial cystitis occurs initially, and then may be accompanied by infectious cystitis. Death due to hemorrhagic cystitis has also been reported occasionally. Bladder edema, lower urinary tract bleeding, interstitial inflammation with fibrosis and bladder fibrosis tendency have also been occasionally observed. Renal impairment (especially in patients with a history of renal insufficiency) occasionally occurs after high-dose infusion.
Note: The combined use of uromitexan can significantly reduce the severity and frequency of urinary tract toxicity caused by cyclophosphamide.

Reproductive system
Cyclophosphamide has an active function of alkylating structures, which is speculated to cause irreversible sperm production disorders, resulting in azoospermia or persistent sperm reduction; ovulation abnormalities, occasionally irreversible ovulation disorders, accompanied by amenorrhea, estrogen decline and related syndromes. Liver: Occasionally, liver dysfunction has been reported, and the corresponding laboratory liver function indicators have increased (SGOT, SGPT, Y-GT, ALP, bilirubin). In bone marrow transplant patients who receive high-dose cyclophosphamide combined with busulfan or whole-body radiotherapy, about 15-50% may develop veno-occlusive disease (VOD). It is rare in patients with aplastic anemia who receive high-dose cyclophosphamide alone. Veno-occlusive disease mainly occurs 1-3 weeks after bone marrow transplantation, with sudden weight gain, hepatomegaly, ascites, hyperbilirubinemia as the main features, and sometimes hepatic encephalopathy.
Known risk factors for the use of VOD include liver dysfunction, hepatotoxic drugs with high-dose continuous chemotherapy, especially pretreatment with busulfan containing an alkylated structure.

Cardiovascular and respiratory system
Some patients have occasional localized pneumonia, interstitial pneumonia and can develop into chronic pulmonary interstitial fibrosis. It has been reported that cytostatic drugs can induce secondary cardiomyopathy, manifested as arrhythmia, electrocardiographic changes and changes in left ventricular ejection fraction (such as myocardial infarction), especially in high-dose cyclophosphamide infusion (120-240mg/kg body weight). It is worth noting that there is clinical evidence that patients receiving radiotherapy near the heart and adjuvant therapy with anthracyclines or valsartan can increase the toxicity of cyclophosphamide to the heart. For this reason, patients with a history of cardiovascular disease must be monitored for water and electrolyte balance and closely observed.

Secondary tumors
In general, cytotoxic drug therapy, including cyclophosphamide chemotherapy, carries a risk of secondary tumors, including precursor manifestations and sequelae. The risk of secondary urethral tumors and the risk of myelodysplasia developing into acute leukemia are relatively high. Animal studies have shown that the appropriate use of uromitexan can significantly reduce the incidence of bladder tumors. Other adverse reactions The most common is hair loss, which is generally reversible. Pigmentation of the palms, nails and soles has also been reported.

The following adverse reactions also occur occasionally:
● SIADH (syndrome of inappropriate antidiuretic hormone secretion. Schwartz-Bartter syndrome) with hyponatremia and water retention
● Some occasional cases have hypersensitivity reactions with fever and development of shock
● Transient blurred vision and dizziness
● Occasional acute pancreatitis
● More rare severe reactions (<0.01%) such as Stevens Jehnsoun syndrome. Toxic exfoliative disease
Note: Other complications such as thrombosis, DIC (disseminated intravascular coagulation) or hemolytic uremic syndrome (HUS) may also be caused by the primary disease. However, including cyclophosphamide in chemotherapy increases their frequency.
Antiemetics and oral hygiene should be taken in a timely manner. Routine blood cell counts should be performed frequently during treatment. Routine monitoring should be performed every 5-7 days at the beginning of chemotherapy. When the white blood cell count is <300/mm3, it should be monitored every 2 days, and if possible, once a day; patients with long-term chemotherapy. Monitor every 2 weeks. Urine sediment should be microscopically examined for red blood cells.

[Contraindications]
Cyclophosphamide should not be used in the following patients;
● Allergic to cyclophosphamide
● Severe bone marrow dysfunction (especially patients who have been treated with cytotoxic drugs and, or radiotherapy)
● Urethral obstruction
● Acute infection
● Pregnancy and lactation. See also precautions
Special treatments and precautions
Before treatment begins, obstructions that affect urine flow should be excluded or corrected, cystitis and infection should be treated, and water and electrolyte disorders should be corrected.
Elderly and frail patients and patients who have received radiotherapy should be closely observed when receiving cyclophosphamide treatment, just like other cytostatic drugs.
Patients with impaired immune function, especially diabetic patients and patients with chronic liver and kidney damage, should be strictly monitored.
During treatment with cyclophosphamide, patients with cystitis and microscopic hematuria and macroscopic hematuria should be interrupted until the patient’s hematuria is corrected.
During treatment, the white blood cell count should be monitored regularly: at the beginning of treatment, the interval is 5-7 days. If the white blood cell count is less than 3000/mm3, monitoring is recommended when the phenomenon occurs. In some cases, it is necessary.
Patients receiving long-term treatment are recommended to monitor every 2 weeks; when any bone marrow suppression occurs, it is recommended to monitor the red blood cell and platelet counts. Urine sediment should be tested regularly to count urine red blood cells.
Effects on driving and operating machines Cyclophosphamide treatment may cause nausea and vomiting, leading to fluid metabolism disorders. Physicians can make recommendations on driving and machine operation based on individual conditions.

[Pregnant women use] Cyclophosphamide treatment can cause abnormal diseases;
In the first three months of pregnancy, if it is a fatal indication, the doctor should be consulted whether the pregnancy should be terminated;
After the first three months of pregnancy, drug treatment cannot be postponed, and the patient should be informed of the possibility of malformation before treatment;
During the treatment period, it should be recommended not to get pregnant, but if you still want to get pregnant during the treatment period, you should receive embryo genetics consultation;
Cyclophosphamide can pass through breast milk, and breastfeeding is not recommended during the treatment period of the mother; Before treatment, men should be warned to store sperm;
The duration of contraception required after treatment should depend on the recovery of the primary disease and the intensity of the patient’s desire to have children.

[Children use]
The safety and effectiveness of this product in pediatric patients have not been determined.

[Drug interactions]
When sulfonylurea antidiabetic drugs are given simultaneously with Andoran, their hypoglycemic effect may be enhanced. Cyclophosphamide may aggravate bone marrow suppression if it is administered simultaneously with allopurinol or hydrochlorothiazide. Previous or combined use of phenobarbital, phenytoin, dihydrobenzoic acid, and hydrochloride may cause induction of liver mitogen-activated enzymes. Due to the immunosuppressive effect of cyclophosphamide, patients may have a reduced response to vaccines when receiving vaccinations, and vaccine-induced infections may occur when active vaccines are injected. If cyclophosphamide treatment is performed while depolarizing muscle relaxants (such as succinylcholine halides) are used, pseudocholinesterase levels may be reduced, and prolonged apnea may occur. If chloramphenicol is used in combination, the half-life of cyclophosphamide may be prolonged and metabolism may be delayed. The combined use of anthracyclines and pentosyl glucoside may enhance the potential cardiotoxicity of cyclophosphamide; previous local radiotherapy to the heart also enhances the cardiotoxicity of cyclophosphamide. The combined use of indomethacin should be used with extreme caution, and there have been individual reports of acute water intoxication. Patients should avoid drinking alcohol and alcoholic beverages during cyclophosphamide chemotherapy. Since grapefruit contains compounds that can interact with cyclophosphamide and reduce its effectiveness, patients should avoid eating grapefruit or beverages containing grapefruit. Contraindications: Benzyl alcohol can reduce the stability of cyclophosphamide.

[Manufacturer]
Aishida Pharmaceutical Factory.